Regenerative Rehabilitation for COVID 19 Sequelae

Regenerative rehabilitation is a relatively new term used to describe the combination between regenerative medicine and rehabilitation therapy. It has been defined as the integration between “regenerative technologies with rehabilitation clinical practices to restitute function and quality of life in individuals with disabilities due to otherwise irreparable tissues or organs damaged by disease or trauma” [1]. Due to the growing interest in this field, the American Physical Therapy Association has defined it as the “the integration of principles and approaches from rehabilitation and regenerative medicine, with the ultimate goal of developing innovative and effective methods that promote the restoration of function through tissue regeneration and repair” [2]. 

While the majority of research has been conducted in musculoskeletal injuries with encouraging early results [3,4], efforts have also been made in other areas as neurorehabilitation showing promising results in conditions with otherwise poor rehabilitation prognosis, including spinal cord injuries or stroke [5,6]. MSC are one of the most studied alternatives in regenerative therapy given their easy obtention and availability and the observed effects in neurological, autoimmune and musculoskeletal conditions [7]. 

As this discipline is still in its early stages, mechanisms of action are yet to be totally understood. Nevertheless, based on knowledge to date in each individual therapy, two main mechanisms have been suggested to explain how regenerative medicine added to rehabilitation may exert its effect: first, MSC have the capacity to differentiate into damaged tissue cells and engraft to it, favoring healing. The second hypothesis, and the most accepted to date, lies in MSC potential to release a wide variety of anti-inflammatory and growth factors with paracrine actions that allows regeneration of affected tissue [8]. 

COVID 19 pandemic has spread rapid over the world, posing a collapse threat to healthcare systems. While Intensive Care Units are cornerstones in early response to the disease, regenerative rehabilitation should play an important role in COVID 19 survivors to prevent disability and to optimize acute inpatient approaches [9,10].

As time passes, new information about COVID 19 consequences have become available. It has been reported that in severe patients without intubation requirement, persistent symptoms such as dyspnea (33%), cough (33%) and fatigue (45%) are common, also finding a decrease in 6 minutes walking distance (79%) without alterations in oxygen saturation [11]. It is know that these patients may have damaged lung parenchyma with fibrosis and alveolar space obliteration [12]. Another report found that 41% of COVID patients after discharge presented at least one persistent symptom at 100 days follow up, being dyspnea the most prevalent (36%), with 21% of patients presenting a decline in diffusing capacity of the Lungs for Carbon Monoxide (DLCO) and 63% of patients still had findings in Chest Computed Tomography (CCT) scans such as ground glass opacity and reticular pattern in lower pulmonary lobes [13]. The scenario is worse in patients requiring mechanical ventilation. In CCT scans, ground glass opacity was present in 89% of patients, and findings indicating pulmonary fibrosis were present in 67% of them [14]. To date, pulmonary fibrosis prevalence has been estimated to be around 7 to 10%, similar to patients Acute Respiratory Distress Syndrome from other causes [15,16]. Looking at SARS-CoV data from 2003 it was described that 28% of patients still had similar findings in CCT a year after diagnosis and pulmonary function improvement plateaued at six months from discharge, with alterations persisting for 2 years [17], situation that has raised concerns about possible similarities with SARS-CoV-2. 

Besides pulmonary sequelae, a German study including 100 patients found that 60% of patients had myocardial inflammation signs in magnetic resonance 71 days after diagnosis [18]. This finding was present even in 46% of athlete patients with no need of hospitalization [19]. 

As if it were not enough, mental health has also been heavily affected by this pandemic, estimating that 18% of Spaniards have depressive symptoms and 21% present with anxiety [20].

Taking into account the previous information, different authors have urged to include early rehabilitation strategies in COVID 19 patients aiming to improve quality of life and lower sequelae impact attempting a rapid recovery [21,22]. It has been shown that cardiopulmonary rehabilitation may help patients improve 6 minute walking distance [23]. Furthermore, a study evaluating pulmonary rehabilitation in patients older than 65 years found that after 6 weeks, treated patients improved in DLCO, spirometry, quality of life and 6 minutes walking distance [24]. China and Italy are now recommending pulmonary or cardiac rehabilitation in post-acute COVID patients. Based on our medical experience in treatment and rehabilitation of post COVID 19 patients, and supported in available literature [9,10,25-27], we suggest the following cardiac and pulmonary rehabilitation exercise (Figures 1 and 2).

 Figure 1: Pulmonary rehabilitation: Two sessions of ten minutes each per week for 4 weeks. 

 Figure 2: Mobility and functional rehabilitation: Strength, maximal oxygen consumption (8 to 12 repetitions, 1 to 4 minutes rest, 3 sessions per week for 4 weeks).

Some case reports and exploratory studies have been published so far in COVID 19 and MSC. First reports from China showed how MSC use in critical patients produced improvements in clinical and paraclinical variables 4 to 7 days after therapy, lowering mortality. These authors also found that MSC do not express ACE 2 receptor, suggesting they cannot be susceptible to SARS-CoV-2 [28,29]. A study in Spain including 13 patients requiring mechanical ventilation found that intravenously infused MSC induced clinical improvements in 70% of patients and 53% of patients were able to be extubated 14 days after first dose  (the majority of patients received 2 doses of 1*10⁶ cells per kilogram of body weight with only a few receiving 3 doses) [30]. Recently, a Chinese study in patients with moderate to severe COVID 19 receiving 3 doses of 3*10⁷ cells found that only 1 patient required mechanical ventilation compared to 4 patients in the control group [31]. No serious adverse events were found in any of these reports. In a randomized control trial involving 24 patients with severe illness, authors found better survival (91% vs 42%), cytokine profile improvement by day 6 and a faster recovery time [32]. This findings added to their regenerative capacities, could prevent long term tissue damage induced by this condition, as they are capable of lowering neutrophil infiltration and release growth factors, mRNA and microRNA that may promote lung tissue repair [33,34]. MSC are also capable of stimulating resident lung MSC into lung epithelial and support cells and also stimulate angiogenesis via vascular endothelial growth factor, basic fibroblastic growth factor and CXCL12, enhancing vascular regeneration [35]. Besides, it has been shown to be safe in pulmonary fibrosis and COPD, modulating immune response in these patients [36-39]. Based on this information, doses of 1*10⁶ cells per kilogram should be used in regenerative rehabilitation research protocols for post COVID symptoms. To the date of writing of this article, clinical trials were yet to be registered in clinicaltrials.gov.

We must consider the threat and challenge that COVID 19 pandemic poses as an opportunity to rearrange and improve rehabilitation services and, at the same time, promote clinical research. We should also be encouraged to implement new therapeutic strategies such as regenerative medicine, MSC therapy and regenerative rehabilitation aiming to improve patient’s quality of life and to alleviate pressure on healthcare systems.

This work was funded by Fundación Don Roberto Fernández Viña and BioXcellerator Medellin.